PMID- 22334021
OWN - NLM
STAT- MEDLINE
DCOM- 20130220
LR  - 20211021
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 20
IP  - 5
DP  - 2012 May
TI  - Lens epithelium-derived growth factor/p75 qualifies as a target for HIV gene 
      therapy in the NSG mouse model.
PG  - 908-17
LID - 10.1038/mt.2012.6 [doi]
AB  - Lens epithelium-derived growth factor (LEDGF/p75) is an essential cofactor of HIV 
      integration. Both stable overexpression of the C-terminal part of LEDGF/p75 
      (LEDGF(325-530)) containing the integrase (IN)-binding domain (IBD) and stable 
      knockdown (KD) of LEDGF/p75 are known to inhibit HIV infection in laboratory cell 
      lines. Here, primary human CD(4)(+) T-cells were transduced with lentiviral 
      vectors encoding LEDGF(325-530), the interaction-deficient mutant 
      LEDGF(325-530)D366N, or a hairpin depleting LEDGF/p75 and challenged with HIV. 
      Maximal protection of primary T-cells from HIV infection was obtained after 
      LEDGF(325-530) overexpression reducing HIV replication 40-fold without evidence 
      of cellular toxicity. This strategy was subsequently evaluated in the 
      NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mouse model. Threefold reduction in 
      mean plasma viral load was obtained in mice engrafted with CD(4)(+) T-cells 
      expressing LEDGF(325-530) in comparison with engraftment with LEDGF(325-530)D366N 
      cells. Four weeks after transplantation with LEDGF(325-530)D366N cells, 70% of 
      the CD(4)(+) cells were lost due to ongoing HIV replication. However, in mice 
      transplanted with LEDGF(325-530) cells only a 20% decrease in CD(4)(+) cells was 
      measured. Liver and spleen sections of LEDGF(325-530) mice contained less HIV 
      than LEDGF(325-530)D366N mice as measured by p24 antigen detection. 
      LEDGF(325-530) overexpression potently inhibits HIV replication in vivo and 
      protects against HIV mediated cell killing of primary CD(4)(+) T-cells.
FAU - Vets, Sofie
AU  - Vets S
AD  - Division of Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
FAU - Kimpel, Janine
AU  - Kimpel J
FAU - Volk, Andreas
AU  - Volk A
FAU - De Rijck, Jan
AU  - De Rijck J
FAU - Schrijvers, Rik
AU  - Schrijvers R
FAU - Verbinnen, Bert
AU  - Verbinnen B
FAU - Maes, Wim
AU  - Maes W
FAU - Von Laer, Dorothee
AU  - Von Laer D
FAU - Debyser, Zeger
AU  - Debyser Z
FAU - Gijsbers, Rik
AU  - Gijsbers R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120214
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (lens epithelium-derived growth factor)
SB  - IM
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/transplantation/*virology
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - HIV/*physiology
MH  - HIV Infections/genetics/*therapy/virology
MH  - Humans
MH  - Injections, Intraperitoneal
MH  - Intercellular Signaling Peptides and Proteins/*genetics
MH  - Lentivirus/genetics
MH  - Mice
MH  - Mice, Transgenic
MH  - Mutation
MH  - Peptide Fragments/genetics
MH  - Transduction, Genetic
MH  - Transplantation, Heterologous
MH  - Virus Integration/genetics
MH  - Virus Replication/genetics
PMC - PMC3345997
EDAT- 2012/02/16 06:00
MHDA- 2013/02/21 06:00
PMCR- 2013/05/01
CRDT- 2012/02/16 06:00
PHST- 2012/02/16 06:00 [entrez]
PHST- 2012/02/16 06:00 [pubmed]
PHST- 2013/02/21 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - S1525-0016(16)31930-X [pii]
AID - 10.1038/mt.2012.6 [doi]
PST - ppublish
SO  - Mol Ther. 2012 May;20(5):908-17. doi: 10.1038/mt.2012.6. Epub 2012 Feb 14.